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Cancer exodus hypothesis

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The cancer exodus hypothesis establishes that circulating tumor cell clusters (CTC clusters) maintain their multicellular structure throughout the metastatic process. It was previously thought that these clusters must dissociate into single cells during metastasis.[1] According to the hypothesis, CTC clusters intravasate (enter the bloodstream), travel through circulation as a cohesive unit, and extravasate (exit the bloodstream) at distant sites without disaggregating, significantly enhancing their metastatic potential. This concept is considered a key advancement in understanding of cancer biology and CTCs role in cancer metastasis.[2][3]

Mechanism

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Traditionally, it was believed that CTC clusters needed to dissociate into individual cells during their journey through the bloodstream to seed secondary tumors. However, recent studies show that CTC clusters can travel through the bloodstream intact, enabling them to perform every step of metastasis while maintaining their group/cluster structure.[3][2][4]

The cancer exodus hypothesis asserts that CTC clusters have several distinct advantages that increase their metastatic potential:

  • Higher metastatic efficiency: CTC clusters have been shown to possess superior seeding capabilities at distant sites compared to single CTCs.[3][5]
  • Survival and proliferation: The collective nature of CTC clusters allows them to share resources and offer intercellular support, improving their overall survival rates in the bloodstream.[6][7]
  • Resistance to treatment: CTC clusters exhibit unique gene expression profiles that contribute to their ability to evade certain cancer therapies, making them more resistant than individual tumor cells.[8][9]

Clinical relevance

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The cancer exodus hypothesis offers important insights into how metastasis occurs and highlights the significance of CTC clusters in cancer progression. Detecting and analyzing CTC clusters through liquid biopsies could offer valuable information about the aggressiveness and metastatic potential of cancers.[10][11] This information is particularly useful for identifying patients who may benefit from more aggressive treatment strategies.[2][12]

Characterization

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The hypothesis was developed due to several key studies, which have demonstrated the ability of CTC clusters to:

  • Intravasate and travel as clusters: Research has shown that CTC clusters can enter the bloodstream as a group, travel through the circulatory system intact, and maintain their cluster phenotype during transit.[13][4][3]
  • Extravasate through angiopellosis: A key finding of the hypothesis is that CTC clusters do not need to disaggregate to exit the bloodstream. Instead, they can undergo a process called angiopellosis, in which entire clusters migrate out of the blood vessels as a group, retaining their multicellular form. [14][2]

These findings underscore the critical role of CTC clusters in driving the metastatic cascade and suggest that CTC clusters could serve as important biomarkers in cancer diagnosis, prognosis, and treatment planning.[5] Additionally, understanding the mechanisms that allow CTC clusters to retain their structure and survive in circulation opens new avenues for targeted cancer therapies designed to disrupt this process.[15]

Future directions

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As research into the cancer exodus hypothesis progresses, new therapeutic strategies could emerge to specifically target CTC clusters. Blocking their formation, disrupting their cohesion, or preventing their ability to survive in the bloodstream could offer new ways to prevent metastasis in aggressive cancers. Continued studies will be essential to further elucidate the biological pathways involved in CTC cluster-mediated metastasis and develop potential treatment interventions.[16][17]

References

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  1. ^ Ring, Alexander; Nguyen-Sträuli, Bich Doan; Wicki, Andreas; Aceto, Nicola (February 2023). "Biology, vulnerabilities and clinical applications of circulating tumour cells". Nature Reviews. Cancer. 23 (2): 95–111. doi:10.1038/s41568-022-00536-4. ISSN 1474-1768. PMC 9734934. PMID 36494603.
  2. ^ a b c d Allen, TA (2019). "Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential". Journal of Cell Science. 132 (17). doi:10.1242/jcs.231563. PMC 6771143. PMID 31409692.
  3. ^ a b c d Aceto, N (2014). "Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis". Cell. 158 (5): 1110–1122. doi:10.1016/j.cell.2014.07.013. PMC 4149753. PMID 25171411.
  4. ^ a b Au, SH; Storey, BD; Moore, JC; Tang, Q; Chen, YL; Javaid, S; Sarioglu, AF; Sullivan, R; Madden, MW; O'Keefe, R; Haber, DA; Maheswaran, S; Langenau, DM; Stott, SL; Toner, M (3 May 2016). "Clusters of circulating tumor cells traverse capillary-sized vessels". Proceedings of the National Academy of Sciences of the United States of America. 113 (18): 4947–52. Bibcode:2016PNAS..113.4947A. doi:10.1073/pnas.1524448113. PMC 4983862. PMID 27091969.
  5. ^ a b Sayed, Zeinab S.; Khattap, Mohamed G.; Madkour, Mostafa A.; Yasen, Noha S.; Elbary, Hanan A.; Elsayed, Reem A.; Abdelkawy, Dalia A.; Wadan, Al-Hassan Soliman; Omar, Islam; Nafady, Mohamed H. (2024-04-01). "Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature". Discover Oncology. 15 (1): 94. doi:10.1007/s12672-024-00949-7. ISSN 2730-6011. PMC 10984915. PMID 38557916.
  6. ^ Schuster, Emma; Taftaf, Rokana; Reduzzi, Carolina; Albert, Mary K.; Romero-Calvo, Isabel; Liu, Huiping (November 2021). "Better together: circulating tumor cell clustering in metastatic cancer". Trends in Cancer. 7 (11): 1020–1032. doi:10.1016/j.trecan.2021.07.001. ISSN 2405-8033. PMC 8541931. PMID 34481763.
  7. ^ Aceto, Nicola; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A. (May 2015). "En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition". Trends in Cancer. 1 (1): 44–52. doi:10.1016/j.trecan.2015.07.006. ISSN 2405-8025. PMID 28741562.
  8. ^ Sarioglu, AF; Aceto, N; Kojic, N; Donaldson, MC; Zeinali, M; Hamza, B; Engstrom, A; Zhu, H; Sundaresan, TK; Miyamoto, DT; Luo, X; Bardia, A; Wittner, BS; Ramaswamy, S; Shioda, T; Ting, DT; Stott, SL; Kapur, R; Maheswaran, S; Haber, DA; Toner, M (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–91. doi:10.1038/nmeth.3404. PMC 4490017. PMID 25984697.
  9. ^ Allen, Tyler A.; Cullen, Mark M.; Hawkey, Nathan; Mochizuki, Hiroyuki; Nguyen, Lan; Schechter, Elyse; Borst, Luke; Yoder, Jeffrey A.; Freedman, Jennifer A.; Patierno, Steven R.; Cheng, Ke; Eward, William C.; Somarelli, Jason A. (2021). "A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation". Frontiers in Oncology. 11: 641187. doi:10.3389/fonc.2021.641187. ISSN 2234-943X. PMC 8495265. PMID 34631514.
  10. ^ Sarioglu, AF; Aceto, N; Kojic, N; Donaldson, MC; Zeinali, M; Hamza, B; Engstrom, A; Zhu, H; Sundaresan, TK; Miyamoto, DT; Luo, X; Bardia, A; Wittner, BS; Ramaswamy, S; Shioda, T; Ting, DT; Stott, SL; Kapur, R; Maheswaran, S; Haber, DA; Toner, M (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–91. doi:10.1038/nmeth.3404. PMC 4490017. PMID 25984697.
  11. ^ Amintas, Samuel; Bedel, Aurélie; Moreau-Gaudry, François; Boutin, Julian; Buscail, Louis; Merlio, Jean-Philippe; Vendrely, Véronique; Dabernat, Sandrine; Buscail, Etienne (2020-04-10). "Circulating Tumor Cell Clusters: United We Stand Divided We Fall". International Journal of Molecular Sciences. 21 (7): 2653. doi:10.3390/ijms21072653. ISSN 1422-0067. PMC 7177734. PMID 32290245.
  12. ^ Lawrence, Rachel; Watters, Melissa; Davies, Caitlin R.; Pantel, Klaus; Lu, Yong-Jie (July 2023). "Circulating tumour cells for early detection of clinically relevant cancer". Nature Reviews. Clinical Oncology. 20 (7): 487–500. doi:10.1038/s41571-023-00781-y. ISSN 1759-4782. PMC 10237083. PMID 37268719.
  13. ^ Cheung, Kevin J.; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D.; Fairchild, Amanda N.; Gorin, Michael A.; Verdone, James E.; Pienta, Kenneth J.; Bader, Joel S.; Ewald, Andrew J. (2016-02-16). "Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters". Proceedings of the National Academy of Sciences of the United States of America. 113 (7): E854–863. Bibcode:2016PNAS..113E.854C. doi:10.1073/pnas.1508541113. ISSN 1091-6490. PMC 4763783. PMID 26831077.
  14. ^ Allen, TA; Gracieux, D; Talib, M; Tokarz, DA; Hensley, MT; Cores, J; Vandergriff, A; Tang, J; de Andrade, JB; Dinh, PU; Yoder, JA; Cheng, K (January 2017). "Angiopellosis as an Alternative Mechanism of Cell Extravasation". Stem Cells (Dayton, Ohio). 35 (1): 170–180. doi:10.1002/stem.2451. PMC 5376103. PMID 27350343.
  15. ^ Taftaf, Rokana; Liu, Xia; Singh, Salendra; Jia, Yuzhi; Dashzeveg, Nurmaa K.; Hoffmann, Andrew D.; El-Shennawy, Lamiaa; Ramos, Erika K.; Adorno-Cruz, Valery; Schuster, Emma J.; Scholten, David; Patel, Dhwani; Zhang, Youbin; Davis, Andrew A.; Reduzzi, Carolina (2021-08-11). "ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer". Nature Communications. 12 (1): 4867. Bibcode:2021NatCo..12.4867T. doi:10.1038/s41467-021-25189-z. ISSN 2041-1723. PMC 8358026. PMID 34381029.
  16. ^ Allen, TA (31 March 2024). "The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance". Cancers. 16 (7): 1377. doi:10.3390/cancers16071377. PMC 11010957. PMID 38611055.
  17. ^ Khoo, Bee Luan; Grenci, Gianluca; Lim, Ying Bena; Lee, Soo Chin; Han, Jongyoon; Lim, Chwee Teck (January 2018). "Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device". Nature Protocols. 13 (1): 34–58. doi:10.1038/nprot.2017.125. ISSN 1750-2799. PMID 29215634.
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